The effects of a brief course of leukapheresis were studied in fourteen patients with Rheumatoid Arthritis, unresponsive to conventional therapy. The patients consisted of two groups-those with profoundly depressed or normal peripheral blood mononuclear cell proliferation of soluble antigens. They represented the extremes of our rheumatoid patient population. Six of 7 patients with depressed proliferation clinically improved, whereas 0/7 patients with normal proliferation clinically improved following a brief (six runs over two weeks) course of leukapheresis. This and other immunologic abnormalities tended to normalize in the group which clinically improved but not the clinically nonresponder group. Thus, reversal of depressed immune function appeared to paralled clinical improvement. These studies provide new insights into the pathogenesis of rheumatoid arthritis and more insight into the effects of leukapheresis.